CN1972946A - 7h-pyrrolo[2,3-d]pyrimidine derivatives, as well as their therapeutically acceptable salts, pharmaceutical preparations containing them and process for production the active agent - Google Patents

7h-pyrrolo[2,3-d]pyrimidine derivatives, as well as their therapeutically acceptable salts, pharmaceutical preparations containing them and process for production the active agent Download PDF

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CN1972946A
CN1972946A CNA2005800206893A CN200580020689A CN1972946A CN 1972946 A CN1972946 A CN 1972946A CN A2005800206893 A CNA2005800206893 A CN A2005800206893A CN 200580020689 A CN200580020689 A CN 200580020689A CN 1972946 A CN1972946 A CN 1972946A
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pyrrolo
dimethyl
pyrimidine
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杰诺斯·苏善宜
拉斯罗·欧飞
乔治·凯瑞
弗赖杰斯·瓦斯泽克
艾瑞克·平特
祖善那·海牙斯
塔玛斯·祖特
约瑟夫·耐迈斯
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Abstract

The invention relates to new 7H-pyrrolo[2,3-d]pyrimidine derivatives, as well as their therapeutically acceptable salts, pharmaceutical preparations containing them and process for producing the active agent. The pharmaceutical preparation is adventageously antiphlogistic and analgetic one, a preparation reducing neuropathic hyperalgesia and rheumatic arthritis, a preparation for hindering destruction of bones chondrus, being applicable for treatment of other diseases, which may be connected with other inflammatory processes e.g. asthma, eczema or psoriasis.

Description

7H-pyrrolo-[2,3-d] pyrimidine derivatives and treat acceptable salt, contain their pharmaceutical preparation and prepare the method for this active substance
The present invention relates to new 7H-pyrrolo-[2,3-d] pyrimidine derivatives and treat acceptable (therapeutically acceptable) salt, contain their pharmaceutical preparation and prepare the method for this active substance.
The compound of general formula (I) is the base substance of following pharmaceutical preparation, and described pharmaceutical preparation comprises preparation with neurogenicity and non-neurogenicity anti-inflammatory and analgesic effect, alleviate the hyperalgesic preparation of neuropathic, be used to prevent rheumatic arthritis or treatment articular bone disorganization or joint cartilage (chondrus) destructive preparation and the preparation that is used for other disease relevant with other inflammatory process---as asthma, eczema, psoriatic---.
The compound of general formula (I) is a new compound.Their typical types can be used general formula (Ia), (Ib) and (Ic) description.
The compound that is different from 7H-pyrrolo-[2, the 3-d] pyrimidine derivatives of above-claimed cpd is known as kinases (quinase) inhibitor and with the antitumor drug of this mode effect in technical literature.
The kinase whose known active 7H-pyrrolo-[2 of above-mentioned inhibition, 3-d] important structure of pyrimidine derivatives is characterised in that, nitrogen-atoms 7 pyrroles is connected in the nitrogen-atoms of the functional amine on 4 with another, have only a nitrogen-atoms that substituting group (J.Med.Chem.39 (1996) 2285-2292, Bioorg.Med.Chem.Letters 11 (2001) 849-852) can be arranged.
For compound of the present invention, all there is substituting group two positions already pointed out.
Therefore, the present invention relates to 7H-pyrrolo-[2, the 3-d] pyrimidine derivatives of general formula (I) and treat acceptable salt.
In general formula (I):
R1 is the alkyl of 1-4 carbon atom of alkyl, morpholino-contain of 1-4 the carbon atom of alkyl, heteroaryl-contain of 1-4 carbon atom of alkyl, aryl, heteroaryl or aryl-contain or dialkyl amido-the contain alkyl of 1-4 carbon atom.
R2, R3 are hydrogen, methyl, ethyl, propyl group, sec.-propyl or cyclopropyl independently of one another, and perhaps R2 and R3 become tetramethylene together.
R4 is
Figure A20058002068900061
Perhaps Perhaps
Figure A20058002068900063
Wherein: R5 for replace or unsubstituted aromatic ring or hetero-aromatic ring, wherein
R6, R7, R8 and R9 are hydrogen, halogen, nitro, amino, alkylamino, dialkyl amido, hydroxyl, methoxyl group, oxyethyl group, isopropoxy or alkylsulfonyl independently,
R10 is hydrogen or itrile group,
R11 is hydrogen, methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl or the tetramethylene ring that links to each other with X,
R12 is the alkyl of 1-4 carbon atom of alkyl, morpholino-contain of 1-4 the carbon atom of alkyl, heteroaryl-contain of 1-4 carbon atom of alkyl, aryl, heteroaryl, aryl-contain or dialkyl amido-the contain alkyl of 1-4 carbon atom,
If R11 is the tetramethylene ring that links to each other with X, then X is a carbon, and in addition X is nitrogen, methyne, methyl-methyne, ethyl-methyne, propyl group-methyne, sec.-propyl-methyne, cyclopropyl-methyne, the tertiary butyl-methyne or phenyl-methyne.
The acceptable salt of described treatment advantageously is acid salt.
The most typical compound of general formula (I) can be by formula (Ia), (Ib) and (Ic) definition, and wherein R1, R2, R3, R5, R6, R7, R8, R9, R10, R11, R12 and X are same as above.
The invention still further relates to general formula (I) compound that contains as active substance and the pharmaceutical preparation for the treatment of acceptable additive.
Described pharmaceutical preparation advantageously for anti-inflammatory and analgesia preparation, alleviate neuropathic hyperpathia and rheumatic arthritis preparation, be used to prevent bone destruction and cartilage destruction preparation, can be used for treating the preparation of other disease---as asthma, eczema or psoriatic---that may be relevant with other inflammatory process.
The invention still further relates to the method for 7H-pyrrolo-[2, the 3-d] pyrimidine derivatives of preparation general formula (I).
Being characterized as of described method, by 3-hydroxyl-2-butanone and etc. the amine of molar equivalent and the compound that propane dinitrile makes general formula (II), wherein R1, R2, R3 are same as above.
Add the 5-10 times of formic acid that quality is excessive, mixture stirs 1 hour to 2 days under reflux temperature, then mixture is poured in the frozen water.With the product separation, the drying that are settled out, the phosphoryl chloride with 5 to 10 times of amounts of described product reacted under reflux temperature 0.5 to 4 hour then, then with mixture extremely on ice.The imido chlorine (imidoyl chloride) of the general formula (III) that wherein R1, the R2, the R3 that are settled out is same as above separates, and makes its drying, evaporation (evapotate), then
A) the imido chlorine of the general formula of gained (III) is dissolved in the aprotic solvent as stated above, and make the general formula (II) or the reaction of amine (IV) of itself and equivalent, its formula of (II) or R1 (IV) and R3 are same as above, add 2-10 times of molar equivalent excessive N aH.Reaction continues 0.5-6 hour.Then extremely on ice, the product that separation and purifying are settled out with mixture.
Perhaps
B) in polar organic solvent, with imido chlorine and 2-10 times of hydrazine hydrate reaction that molar equivalent is excessive of the general formula of gained (III) as stated above, isolate the reaction product in the organic phase then, dry, evaporation organic phase, then with non-polar solvent with its grinding (bruise).The hydrazine derivative of Sheng Chenging mixes with polar solvent thus, and the aldehyde that makes itself and equivalent is 20-120 ℃ of reaction 1-12 hour down, reaction product isolated then.
Perhaps
C) will be by B) hydrazine derivative of method preparation mixes with polar organic solvent, and reacts, then reaction product isolated with the isatin of equivalent.
The compound of general formula (II) prepares as follows: make 3-hydroxyl-2-butanone and amine that waits molar equivalent and propane dinitrile reaction.According to said method make the compound of general formula (II).Use acidity or basic catalyst, can in same reaction mixture, carry out two-step reaction.
In the first step, use the water sepn annexation, all the time use an acidic catalyst (dense HCl or toluenesulphonic acids), 3-hydroxyl-2-butanone and suitable amine (advantageously in toluene or benzene) in aprotic solvent are reacted under reflux temperature to the water of all generations all to be removed, add propane dinitrile then, and make mixture remain on reflux temperature until the water of removing equivalent.
If use the amine of phenyl amines, then change solvent into protonic solvent, advantageously be methyl alcohol, ethanol or Virahol, and use alkaline medium (KOH or the NaOH aqueous solution) that the amine of phenyl amines and propane dinitrile are reacted in inert atmosphere.
The mixture cooled and filtered goes out the midbody compound of general formula (II), and then that itself and 5-10 times of quality is excessive formic acid (85-98 quality %) mixed under reflux temperature 1 hour to 2 days.With mixture to frozen water, by the product that filters or come precipitation separation to go out with the ethyl acetate extraction of neutral pH.
In both cases all with the product thorough drying, then that product and 5-10 times of quality is excessive phosphoryl chloride reacted 0.5-4 hour under reflux temperature.The mixture that will contain phosphoryl chloride transfers pH to neutral on ice, and the imido chlorine of the general formula (III) that is settled out is leached, or use ethyl acetate extraction, then with organic phase drying, the evaporation of merging.With filter or extraction and evaporation after general formula (III) the imido chlorine that obtains be dissolved in the aprotic solvent (THF, diox, DMSO or DMF) or in their mixture.
At method A) in, add 2-10 times of molar equivalent excessive N aH, the imido chlorine of general formula (III) and the general formula (II) or the amine (IV) of equivalent were reacted 0.5 to 6 hour.Reaction mixture to frozen water, and is dealt with it, the product that filtering-depositing goes out, crystallization obtains the compound of general formula (Ia) Cong diox-ethyl acetate-hexanes mixtures.
At method B) in, make (advantageously in methyl alcohol, ethanol, Virahol, DMF, DMSO or in the mixture of the arbitrary proportion of these solvents) reaction in polar organic solvent of the excessive hydrazine hydrate of the imido chlorine of the general formula of gained (III) as stated above and 2-10 times of molar equivalent, removal of solvent under reduced pressure afterwards, the product of method gained separates between ethyl acetate and water thus then.
Dry back evaporation organic phase, handle residuum with non-polar solvent (advantageously being hexane or ether) and obtain hydrazine derivative, itself and aldehyde (advantageously in methyl alcohol, ethanol, Virahol, DMF, DMSO solvent or in Glacial acetic acid) in polar organic solvent were reacted 1-12 hour under 20-100 ℃ temperature.If solvent has been carried out suitably selecting, product will precipitate and can separate in the mixture cooled and filtered so.
With the compound that obtains general formula (Ib) after non-polar solvent (advantageously being ether or the hexane) washing.
Method C) undertaken by similar approach, just hydrazine derivative is to react with isatin.
The compound of general formula (Ic) according to said method prepares.
Employed in the methods of the invention midbody compound, they are as the midbody product of above-mentioned kinase inhibitor compounds---as im2_1 to im3_3, im3_5 and im4_1 to 4---this part be known, they some be new, as compound given among embodiment 3,5,6 and the 8-11 (seeing Table 1).
Essence of the present invention also is based on such cognition, promptly by using embodiment 4 described methods, the reactive intermediate product of known organism active compound is linked together, can produce new structure, and obtain to have the novel compound of the effect very different with known compound.
The essence of the method for embodiment 4, be general formula (II) and the amine (IV) that is dissolved in anhydrous dimethyl sulphoxide can be transformed into sodium salt by adding sodium hydride, and described salt can at room temperature combine with the imido chlorine of general formula (III) expression, can obtain the compound of general formula (Ia) by this method.
Imido chlorine and heterocyclic radical amine being connected in the presence of sodium hydride, and the pyrazolyl aminoderivative that obtains and the unknown in the literature of pyrryl aminoderivative.
Compound with identical biological action also can obtain as follows: the imido chlorine by general formula (III) expression at first reacts with hydrazine hydrate in containing the alcoholic acid medium, then as described in embodiment 7 and the 12-15, thus obtained 4-diazanyl-7H-pyrrolo--[2,3-d] pyrimidine derivatives and aldehyde or isatin reaction, obtain general formula (Ib) or compound (Ic) thus.
The condensation reaction in containing the alcoholic acid medium of phenyl aldehyde and isatin is known by document, but can be by 4-diazanyl-7H-pyrrolo-[2,3-d] among the hydrazone that obtains of pyrimidine derivatives, only on 5, there is the above-mentioned hydrazone of phenyl substituent on the books at present (J.Chem.Res.Miniprint 12 (1997) 2771-2789).
Confirmed that these known 5-phenyl derivatives are invalid fully in inflammatory model of the present invention.
Table 1
General formula The midbody compound numbering R1 R2 R3 Reference
II Im2_1 Benzyl Methyl Methyl J.Med.Chem.39 (1996)2285-2292DE 2818676(1978)
II Im2_2 Benzyl Tetramethylene
II Im2_3 Benzyl Phenyl Phenyl
II Im2_4 The 3-chloro-phenyl- Methyl Methyl
II Im2_5 Dimethylaminopropyl Methyl Methyl
III Im3_1 Benzyl Methyl Methyl
III Im3_2 Benzyl Tetramethylene
III Im3_3 Benzyl Phenyl Phenyl
III Im3_4 The 3-chloro-phenyl- Methyl Methyl Embodiment 3
III Im3_5 Benzyl Four methynes J.Med.Chem.39 (1996)2285-2292
IV Im4_1 Phenyl - The tertiary butyl Bioorg.Med.Chem.
IV Im4_2 The 3-chloro-phenyl- - The tertiary butyl
IV Im4_3 The 3-nitrophenyl - The tertiary butyl
IV Im4_4 The 4-nitrophenyl - The tertiary butyl
IV Im4_5 The 3-methoxyl group - The tertiary butyl
IV Im4_6 The 4-methoxyl group - The tertiary butyl
Compound of the present invention is analgesia and anti-inflammatory compound, and they can be potential oral administration compound.
The possibility of following neurogenic inflammation has appearred preventing,---as P material (SP) or calcitonin-gene-related peptide (CGRP)---has vital role by the elementary sensory neuropeptide of importing release in the described inflammation, and, on the basis that seven peptide somatostatin analogue TT-232 validity are investigated, the possibility of new type analgesic has appearred finding also.
According to previous investigation situation, find that TT-232 is the effective anodyne that prevents neurogenicity and non-neurogenic inflammation, it is also effective in neuropathic nocuity model.Because TT-232 is a peptide structure and can not oral absorption, therefore the clinical trial that has begun this compound is simultaneously investigated investigating its peptide analogy thing, thereby but finds a kind of oral absorption and have the compound of Broadspectrum antiphlogistic analgesic activity similarly with TT-232.
Sensory neurone element (element) to isolating rat tracheae carries out electricity irritation to carry out experiment in vitro.Under the influence that stimulates, discharge medium---the P material of neurogenic inflammation, can measure P material concentration in the water-bath by radioimmunoassay by the capsaicin-sensitive neurons element.Somatostatin antagonists and TT-232 stop the terminal nerve excitement, thereby make that the neuropeptide quantitative change that discharges in the water-bath is few.
About TT-232 the experiment of the antiinflammation of neurogenicity and non-neurogenic inflammation once was primarily aimed at rat and carried out (exoserosis, dextran (dextrane) oedema, freund's adjuvant inductive chronic arthritis oedema, bradykinin (bradyquinine) the inductive joint slurries that bring out as tori seed oil ooze out, under carrageenin (carrageenine) oedema, carrageenin influence leukocyte recruitment).In the described Bioexperiment of patent specification, with the alcoholic solution inducing mouse dropsy of ear of capsaicine, and the quality by the measurement ear and Evans Blue (Evans ' s blue) accumulation level comes the above-mentioned oedema degree of quantitative evaluation.
Before on the Wistar female rats, confirmed the antiinflammation of TT-232 to freund's adjuvant inductive chronic inflammatory diseases.This model is the rheumatic arthritis experimental model.The patient who suffers from rheumatic arthritis had been carried out in 2004 the II clinical trial phase of TT-232.Consider that it is symptom of rats that freund's adjuvant has increased the weight of Lewis, be that Lewis is the remarkable distortion in rat joint, so, also investigated TT-232 to bone destruction, to the synovial membrane lymphocyte with white corpuscle filters and to the Influence and Development of mechanical hyperalgesia except investigating by the arthroncus of freund's adjuvant inductive.
In the described experiment of patent specification, used with lower device.
Obtained NMR figure by Bruker AC300 device.
The device that is used for the HPLC detection is:
Has Waters HPLC Supelco Discovery RP-Amide C16 post and that have ZMD MS detector and Waters 996 DAD UV detectors, wherein acetonitrile gradient is per 6 minutes 10 to 100% (formic acid content 0.05%), and flow velocity is per minute 3ml.
B ü chi Melting Point B-540 device is used to measure fusing point.
In following examples narration compound of the present invention, prepare their method and determine the experiment of their effectiveness.
Embodiment 1
Preparation 2-amino-4, the method for 5-dimethyl-1-(3-chloro-phenyl-)-1H-pyrrolo--3-formonitrile HCN
18g (0.2mol) 3-hydroxyl-2-butanone and 21ml (0.2mol) 3-chloroaniline are dissolved in the 300ml toluene, add the dense HCl of 0.2ml then.Reaction mixture refluxed under atmospheric pressure is evaporated to half volume after two and one-half-hours, last vacuum is steamed and removed all solvents.The material that obtains is dissolved in the 350ml ethanol, adds earlier 13.2ml (0.2mol) propane dinitrile, the back is dissolved in the solution of 50ml water to wherein dripping 11.2g KOH, with ice-cooled.2 hours postcooling of mixture backflow.Filter the crystallized product of gained, with hexane wash (45.2g; 92%).
Embodiment 2
Preparation 5, the method for 6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-alcohol (ole)
40g 2-amino-4,5-dimethyl-1-(3-chloro-phenyl-) amino-3-cyano group-pyrroles (embodiment 1) refluxed 10 hours in 200g formic acid.Afterwards with mixture on ice, and stirred 1 hour.The material that is settled out is filtered water washing.Product is in drying at room temperature, is not further purified promptly to be used for next reaction (27g; 60%).
Embodiment 3
Preparation 5, the method for 6-dimethyl-4-chloro-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine.
With 26.9g 4-hydroxyl-5,6-dimethyl-7-((3-chloro-phenyl-) amino) pyrrolo-[2,3-d] pyrimidine (embodiment 2) is dissolved in 125ml POCl 3In, after mixture refluxed 1 hour to volume at least greater than in its excessive far away frozen water of 10 times, POCl 3Leach the product that is settled out after decomposing fully, washing, dry (26.28g; 92%).
Embodiment 4
The method of preparation [the 5-tertiary butyl-2-(3-nitro-phenyl)-2H-pyrazole-3-yl]-[7-(3-chloro-phenyl-)-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-amine
With 0.292g (1mmol) 5,6-dimethyl-4-chloro-7-((3-chloro-phenyl-) amino) pyrrolo-[2,3-d] pyrimidine (embodiment 3) and 0.26g (1mmol) the 5-tertiary butyl-2-(3-nitro-phenyl)-2H-pyrazole-3-yl-amine (im4_3) is dissolved in the 4ml dimethyl sulfoxide (DMSO), gradation adds the 200mg sodium hydride in the violent mixing process, then with mixture mixed at room temperature 1 hour.Reaction mixture on ice, is filtered out the settling that is settled out, and with its recrystallization (0.31g in the mixture of ethyl acetate and hexane; 60%).
Embodiment 5
The method of preparation [7-(3-chloro-phenyl-)-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazine
2.92g coexisting, (10mmol) 4-chloro-7-(3-chloro-phenyl-)-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine (embodiment 3) and 3ml hydrazine hydrate one boiled underpressure distillation solvent and unnecessary hydrazine hydrate 3 hours in the 30ml ethanol.Residuum after the evaporation is divided into water and ethyl acetate layer.To evaporate after the organic layer drying.The residuum of evaporation grinds with ether, obtains [7-(3-chloro-phenyl-)-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazine (1.9g thus; 66%).
Embodiment 6
The method of preparation [7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazine.
Prepare titled reference compound according to embodiment 5 described methods, difference is that raw material is known intermediate product im3_1 (a 2.71g raw material).
(1.92g；74％)
Embodiment 7
Preparation 4-{[5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazono--methyl }-benzene-1, the method for 2-glycol (diole)
With 0.287g (1mmol) [7-(3-chloro-phenyl-)-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazine (embodiment 5) and 0.138g (1mmol) 3,4-dihydroxyl-phenyl aldehyde boiled in 4ml ethanol 6 hours, with the product that is settled out---be 4-{[7-(3-chloro-phenyl-)-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-the hydrazono-methyl }-benzene-1, the 2-glycol---filter and with ether washing (0.29g; 68%).
Embodiment 8
Preparation 2-amino-4, the method for 5-dimethyl-1-(3-morpholine-4-base-propyl group)-1H-pyrroles-3-formonitrile HCN.
In comprising the device of attached water separator, 3-hydroxyl-2-butanone (2-hydroxyl-3-butanone) and 14.4ml (0.1mol) 4-(3-aminopropyl) morpholine of 8.8g (0.1mol) are dissolved in the 170ml toluene, after adding the 0.1ml concentrated hydrochloric acid, mixture is refluxed, 110 ℃ of boilings, add 6.6ml propane dinitrile (malonitrile) after the short period of time cooling until it.Mixture is refluxed, 110 ℃ of boilings, filter cooling until it then through Cellit.The crystal that filtering-depositing goes out (17.31g, 66%).
Embodiment 9
Preparation 5, the method for 6-dimethyl-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-alcohol.
3.761g (14.33mmol) 2-amino-4,5-dimethyl-1-(3-morpholine-4-base-propyl group)-1H-pyrrolo--3-formonitrile HCN (embodiment 8) refluxes in 38ml formic acid and spends the night.Dilute with water mixture in this process, and use NaHCO 3Neutralization is shaken out with the ethyl acetate vibration, with the organic phase evaporation, handles the crystal that is settled out with hexane then, filters (3.265g then; 78.5%).
Embodiment 10
Preparation 5, the method for 6-dimethyl-4-chloro-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine.
3g (10.33mmol) 5,6-dimethyl-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-alcohol (embodiment 9) is at 15ml POCl 3The middle backflow 1 hour.Mixture on ice, is used NaHCO 3Evaporation is shaken out in neutralization with the ethyl acetate vibration.Obtain brown oil (2.71g; 85%).
Embodiment 11
The method of preparation [5,6-dimethyl-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazine.
With 1.785g (5.78mmol) 5,6-dimethyl-4-chloro-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine (embodiment 10) is dissolved in the ethanol of the amount (120ml) that just enough forms solution, add the 17.8ml hydrazine hydrate subsequently, the about 15min of mixture backflow, evaporate then, and it is divided into water and ethyl acetate layer.Dry, evaporation organic phase.The crystal that is settled out in the evaporative process is ground with hexane, filter (1.07g then; 61%).
Embodiment 12
Preparation 4-{[5,6-dimethyl-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-the hydrazono-methyl }-method of pyrocatechol (katechole).
With 304.4mg (1mmol) [5,6-dimethyl-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazine (embodiment 11) and 138.1mg (1mmol) 3,4-dihydroxyl-phenyl aldehyde refluxes half an hour after being dissolved in 6ml ethanol.Leach sedimentary crystal, use ethanol and hexane wash (45%) then.
Embodiment 13
Preparation 4-{[5,6-dimethyl-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl] the hydrazono-methyl }-method of 2-nitro-phenol.
304mg (1mmol) [5,6-dimethyl-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazine (embodiment 11) and 169mg (1mmol) 3-nitro-4 hydroxyls-phenyl aldehyde refluxed 4 hours in 6ml ethanol, cooling then, filter, with ethanol and hexane wash (176mg; 36%).
Embodiment 14
Preparation 4-{[5,6-dimethyl-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-the hydrazono-methyl }-method of 2-methoxyl group-phenol.
304mg (1mmol) [5,6-dimethyl-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazine (embodiment 11) and 152mg (1mmol) Vanillin reflux in 6ml ethanol, leaches sedimentary crystal afterwards, with ethanol and hexane wash (221.37mg; 50%).
Embodiment 15
Preparation 4,6-two chloro-3-{[5,6-dimethyl-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazono-}-1, the method for 3-dihydro-indol-2-one (indole-2-on).
With 108mg (0.5mmol) 4,6-two chloro-isatin add in 152.2mg (0.5mmol) [5,6-dimethyl-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazine (embodiment 11), and mixture refluxes in 4ml ethanol.Leach sedimentary safran crystal, use ethanol and hexane wash (102mg then; 40%).
Embodiment 16
The method of preparation [the 5-tertiary butyl-2-(3-nitro-phenyl)-2H-pyrazole-3-yl]-[5,6-dimethyl-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-amine.
With 650mg (2.5mmol) the 5-tertiary butyl-2-(3-nitro-phenyl)-2H-pyrazole-3-yl-amine and 722mg (2.5mmol) 5,6-dimethyl-4-chloro-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine (embodiment 10) is dissolved among the 4ml DMSO, add 200mg NaH then, mixture stirring at room half an hour, then with mixture on ice.Mixture is extracted dry and evaporation with EtOAc.The brown oil that post is separating obtained, the evaporation back grinds the yellow crystals (272.2mg that filtering-depositing goes out with hexane; 20%).
Embodiment 17 to 19
Provide the chemical formula and the preparation method of embodiment compound in the table 2, provided the physics and the chemical property of compound in the table 3.
Embodiment 92
The method of preparation [the 5-tertiary butyl-2-(4-methoxyl group-phenyl)-2H-pyrazole-3-yl]-[5,6-dimethyl-7-(6-methyl-pyridine-2-yl)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-amine hydrochlorate.
The compound of 48mg embodiment 91 is dissolved in the no Shui diox of 1ml, in mixture, adds the diethyl ether solution of 0.2ml 4M hydrochloric acid.Filter out sedimentary yellow settling, and wash (36mg with ether; 70%), fusing point is 97-98 ℃.
Table 2
The embodiment numbering Chemical name Chemical formula Molecular weight The preparation method's (embodiment numbering) who uses The midbody product (embodiment numbering) that uses Commercially available and the bibliographical information raw material that uses Productive rate (%)
1 2-amino-1-4,5-dimethyl-(3-chloro-phenyl-)-1H-pyrrolo--3-formonitrile HCN C13H12ClN3 245.7137 1 Propane dinitrile, 3-hydroxyl-2-butanone and 3-chloroaniline 92
2 5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-alcohol C14H12ClN3O 273.7242 2 1 60
3 5,6-dimethyl-4-chloro-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine C14H11Cl2N3 292.1699 3 2 92
4 [the 5-tertiary butyl-2-(3-nitro-phenyl)-2H-pyrazole-3-yl]-[5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-amine C27H26ClN7O2 516.007 4 Im3_4 and im4_3 60
5 [5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazine C14H14ClN5 287.7542 5 3 66
6 (7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-hydrazine C15H17N5 267.3362 6 im3_1 74
7 4-{[5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-the hydrazono-methyl }-pyrocatechol (pyrokatechine) C21H18ClN5O2 407.8629 7 5 3,4-dihydroxyl-phenyl aldehyde 68
8 2-amino (amineo)-4,5-dimethyl-1-(3-morpholine-4-base-propyl group)-1H-pyrroles-3-formonitrile HCN C14H22N4O 262.3576 8 66
9 5,6-dimethyl-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-alcohol C15H22N4O2 290.3682 9 8 79
10 5,6-dimethyl-4-chloro-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine C15H21ClN4O 308.8138 10 9 85
11 [5,6-dimethyl-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazine C15H24N6O 304.3981 11 10 61
12 4-{[5,6-dimethyl-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-the hydrazono-methyl }-pyrocatechol C22H28N6O3 424.5069 12 3,4-dihydroxyl-phenyl aldehyde 45
13 4-{[5,6-dimethyl-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-the hydrazono-methyl }-2-nitro-phenol C22H27N7O4 453.505 13 11 4-hydroxyl-3-nitro-phenyl aldehyde 36
14 4-{[5,6-dimethyl-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-the hydrazono-methyl }-2-methoxyl group-phenol C23H30N6O3 438.534 14 11 4-hydroxyl-3-methoxyl group-phenyl aldehyde 50
15 4,6-two chloro-3-{[5,6-dimethyl-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazono-}-1,3-dihydro-indol-2-one (on) C23H25Cl2N7O2 502.4074 15 11 4,6-two chlorisatides 41
16 5-tertiary butyl 2-(3-nitro-phenyl)-2H-pyrazole-3-yl]-[5,6-dimethyl-7-(3-morpholine-4-base-propyl group)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-amine C28H36N8O3 532.6509 16 10 im4_3 20
17 N-(7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl) N '-(2-methoxyl group-benzylidene)-hydrazine C23H23N5O 385.4727 7 6 2-methoxyl group-phenyl aldehyde 54
18 4-[(7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-the hydrazono-methyl]-pyrocatechol C22H21N5O2 387.445 7 6 3,4-dihydroxyl-phenyl aldehyde 62
19 N-[5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-N '-naphthalene-1-base-methylene radical-hydrazine C25H20ClN5 425.9247 7 5 Naphthyl (naphtyl)-1-formaldehyde (carbaldehyde) 35
20 N-[5,6 dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-N '-(4-trifluoromethyl-benzylidene)-hydrazine C22H17ClF3N5 443.8625 7 5 4-trifluoromethyl-phenyl aldehyde 62
21 4-{[5,6 dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-the hydrazono-methyl }-2-nitro-phenol C21H17ClN6O3 436.861 7 5 4-hydroxyl-3-nitro-phenyl aldehyde 33
22 N-(3,4-pair-benzyloxy (benzylxoi)-benzylidene)-N '-[5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazine C35H30ClN5O2 588.1147 7 5 3,4-benzyloxy-phenyl aldehyde 58
23 N-[5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-N '-(3-nitro-benzylidene)-hydrazine C21H17ClN6O2 420.8616 7 5 3-nitro-phenyl aldehyde 72
24 4-{[5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-the hydrazono-methyl }-2-methoxyl group-phenol C22H20ClN5O2 421.89 7 5 4-hydroxyl-3-methoxyl group-phenyl aldehyde 35
25 N-(7-benzyl-5,6-dimethyl-7H--pyrrolo-[2,3-d] pyrimidine-4-yl)-N '-naphthalene (naftal é n)-1-base-methylene radical-hydrazine C26H23N5 405.5067 7 6 Naphthyl-1-formaldehyde 58
26 N-(7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-N '-(4-trifluoromethyl-benzylidene)-hydrazine C23H20F3N5 423.4446 7 6 4-trifluoromethyl-phenyl aldehyde 81
27 N-(7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-N '-thiophene-2-base-methylene radical-hydrazine C20H19N5S 361.4719 7 6 Thiophene-2-formaldehyde 57
28 4-[(7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-the hydrazono-methyl]-2-nitro-phenol C22H20N6O3 416.4431 7 6 4-hydroxyl-3-nitro-phenyl aldehyde 95
29 4-[(7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-the hydrazono-methyl]-2,6-dimethyl-phenol C24H25N5O 399.4998 7 6 3,5-dimethyl-4-hydroxyl-phenyl aldehyde 91
30 N-(7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-N '-(3,4-pair-benzyloxy-benzylidene)-hydrazine C36H33N5O2 567.6967 7 6 3,4-benzyloxy-phenyl aldehyde 67
31 4-[(7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-the hydrazono-methyl]-phenyl }-dimethylamine C24H26N6 398.515 7 6 4-dimethylamino-phenyl aldehyde 21
32 N-(7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-N '-(3-nitro-benzylidene)-hydrazine C22H20N6O2 400.4437 7 6 3-nitro-phenyl aldehyde 25
33 4-[(7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-the hydrazono-methyl]-2-methoxyl group-phenol C23H23N5O2 401.4721 7 6 4-hydroxyl-3-methoxyl group-phenyl aldehyde 20
34 N-(7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-N '-(4-sec.-propyl (izopropyl)-benzylidene)-hydrazine C25H27N5 397.5274 7 6 4-sec.-propyl-phenyl aldehyde 58
35 4-[(7-benzyl-5 ,-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-the hydrazono-methyl]-benzonitrile C23H20N6 380.4561 7 6 4-cyano group-phenyl aldehyde 69
36 4-{[5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-the hydrazono-methyl }-2,6-dimethyl-phenol C23H22ClN5O 419.9177 7 5 3,5-dimethyl-4-hydroxyl-phenyl aldehyde 47
37 4-{[5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-the hydrazono-methyl }-benzonitrile C22H17ClN6 400.874 7 5 4-cyano group-phenyl aldehyde 62
38 5-bromo-3-{[5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazono-}-1, the 3-dihydro-indol-2-one C22H16BrClN6O 495.7694 7 5 5-bromo-isatin 50
39 3-{[5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazono-}-1, the 3-dihydro-indol-2-one C22H17ClN6O 416.8734 7 5 Isatin 33
40 5-chloro-3-{[5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazono-}-1, the 3-dihydro-indol-2-one C22H16Cl2N6O 451.3184 7 5 5-chloro-isatin 63
41 4,7-two chloro-3-{[5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazono-}-1, the 3-dihydro-indol-2-one C22H15Cl3N6O 485.7635 7 5 4,7-chloro-isatin 78
42 3-{[5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazono-}-the 5-methyl isophthalic acid, the 3-dihydro-indol-2-one C23H19ClN6O 430.9005 7 5 5-methyl-isatin 63
43 3-{[5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazono-}-5-fluoro-1, the 3-dihydro-indol-2-one C22H16ClFN6O 434.8638 7 5 5-fluoro-isatin 72
44 3-{[5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-hydrazono-}-5-trifluoromethoxy-1, the 3-dihydro-indol-2-one C23H16ClF3N6O2 500.8712 7 5 5-trifluoromethoxy-isatin 69
45 3-[(7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-hydrazono-]-5-bromo-1, the 3-dihydro-indol-2-one C23H19BrN6O 475.3515 7 6 5-bromo-isatin 46
46 3-[(7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-hydrazono-]-1, the 3-dihydro-indol-2-one C23H20N6O 396.4555 7 6 Isatin 47
47 3-[(7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-hydrazono-]-2-oxygen-2,3-dihydro-1H-indoles-5-sulfonic acid C23H20N6O4S 476.5177 7 6 Isatin-5-sulfonic acid 15
48 3-[(7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-hydrazono-]-5-chloro-1, the 3-dihydro-indol-2-one C23H19ClN6O 430.9005 7 6 5-chloro-isatin 55
49 3-[(7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-hydrazono-]-4,6-two chloro-1, the 3-dihydro-indol-2-one C23H18Cl2N6O 465.3455 7 6 4,6-two chloro-isatin 81
50 3-[(7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-hydrazono-]-4,7-two chloro-1,3-dihydro-indol-2-one C23H18Cl2N6O 465.3455 7 6 4,6-two chloro-isatin 48
51 (7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-(the 5-tertiary butyl-2-phenyl-2H-pyrazole-3-yl)-amine C28H30N6 450.5915 4 Im3_1 and im4_1 33
52 (7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-[the 5-tertiary butyl-2-(4-nitro-phenyl)-2H-pyrazole-3-yl]-amine C28H29N7O2 495.589 4 Im3_1 and im4_4 71
53 (7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-[the 5-tertiary butyl-2 (3-nitro-phenyl)-2H-pyrazole-3-yl]-amine C28H29N7O2 495.589 4 Im3_1 and im4_3 12
54 (7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-yl)-[the 5-tertiary butyl-2-(3-fluoro-phenyl)-2H-pyrazole-3-yl]-amine C28H29FN6 468.5819 4 Im3_1 and im4_2 81
55 (the 5-tertiary butyl-2-phenyl-2H-pyrazole-3-yl)-[5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-amine C27H27ClN6 471.0094 4 Im3_4 and im4_1 57
56 [(the 5-tertiary butyl-2-(3-fluorophenyl)-2H-pyrazoles-3-yl]-[5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-amine C27H26ClFN6 488.9999 4 Im3_4 and im4_2 95
57 [(the 5-tertiary butyl-2-(4-nitro-phenyl)-2H-pyrazole-3-yl]-[5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-yl]-amine C27H26ClN7O2 516.007 4 Im3_4 and im4_4 91
58 (9-benzyl-6,7,8,9-tetrahydrochysene-5H-1,3,9-three nitrogen-fluorenes (fluoren)-4-yl)-[the 5-tertiary butyl-2-(3-fluoro-phenyl)-2H-pyrazole-3-yl]-amine C30H31FN6 494.6202 4 Im3_2 and im4_2 67
59 (9-benzyl-6,7,8,9-tetrahydrochysene-5H-1,3,9-three nitrogen-fluorenes-4-yl)-(the 5-tertiary butyl-2-phenyl-2H-pyrazole-3-yl)-amine C30H32N6 476.6297 4 Im3_2 and im4_1 59
60 5,6-dimethyl-1-(3-chloro-phenyl-)-2-[7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-base-amino]-4,5-dimethyl-1 H-pyrroles (pyrrol)-3-formonitrile HCN C27H22Cl2N6 501.4226 4 Im2_4 and im3_4 69
61 1-benzyl-2-[7-(3-chloro-phenyl-)-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-base-amino]-4,5,6,7-tetrahydrochysene (tetrahidro)-1H-indole-3-formonitrile C30H27ClN6 507.0429 4 Im2_2 and im3_4 66
62 1-benzyl-2-[5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-base-amino]-4,5-phenylbenzene-1H-pyrroles-3-formonitrile HCN C38H29ClN6 605.148 4 Im2_3 and im3_4 60
63 1-benzyl-2-[5,6-dimethyl-7-(3-chloro-phenyl-)-7H-pyrrolo-[2,3-d] pyrimidine-4-base-amino]-4,5-dimethyl-1H-pyrroles-3-formonitrile HCN C28H25ClN6 481.0047 4 Im2_1 and im3_4 74
64 2-(9-benzyl-9H-1,3,9-three nitrogen-fluorenes-4-base-amino)-1-(3-chloro-phenyl-)-4,5-dimethyl-1H-pyrroles-3-formonitrile HCN C30H23ClN6 503.011 4 Im2_4 and im3_5 69
65 1-benzyl-2-(9-benzyl-9H-1,3,9-three nitrogen-fluorenes-4-base-amino)-4,5,6,7-tetrahydrochysene-1H-indole-3-formonitrile C33H28N6 508.6313 4 Im2_2 and im3_5 68
66 1-benzyl-2-(9-benzyl-9H-1,3,9-three nitrogen-fluorenes-4-base-amino)-4,5-two-phenyl-1H-pyrroles-3-formonitrile HCN C41H30N6 606.7365 4 Im2_3 and im3_5 70
67 1-benzyl-2-(9-benzyl-9H-1,3,9-three nitrogen-fluorenes-4-base-amino)-4,5-dimethyl-1H-pyrroles-3-formonitrile HCN C31H26N6 482.5931 4 Im2_1 and im3_5 73
68 2-(9-benzyl-6,7,8,9-tetrahydrochysene-5H-1,3,9-three nitrogen-fluorenes-4-base-amino)-4,5-dimethyl-1-(3-chloro-phenyl-)-1H-pyrroles-3-formonitrile HCN C30H27ClN6 507.0429 4 Im2_4 and im3_2 68
69 1-benzyl-2-(9-benzyl-6,7,8,9-tetrahydrochysene-5H-1,3,9-three nitrogen-fluorenes-4-base-amino)-4,5,6,7-tetrahydrochysene-1H-indole-3-formonitrile C33H32N6 512.6632 4 Im2_2 and im3_2 48
70 1-benzyl-2-(9-benzyl-6,7,8,9-tetrahydrochysene 5H-1,3,9-three nitrogen-fluorenes-4-base-amino)-4,5-phenylbenzene-1H-pyrroles-3-formonitrile HCN C41H34N6 610.7683 4 Im2_3 and im3_3 55
71 1-benzyl-2-(9-benzyl-6,7,8,9-tetrahydrochysene-5H-1,3,9-three nitrogen-fluorenes-4-base-amino)-4,5-dimethyl-1H-pyrroles-3-formonitrile HCN C31H30N6 486.625 4 Im2_1 and im3_2 81
72 2-(7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-base-amino)-1-(3-chloro-phenyl-)-4,5-dimethyl-1H-pyrroles 3-formonitrile HCN C28H25ClN6 481.0047 4 Im2_4 and im3_1 91
73 1-benzyl-2-(7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-base-amino)-4,5,6,7-tetrahydrochysene-1H-indole-3-formonitrile C31H30N6 486.625 4 Im2_2 and im3_1 67
74 1-benzyl-2-(7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-base-amino)-4,5-phenylbenzene-1H-pyrroles-3-formonitrile HCN C39H32N6 584.7301 4 Im2_3 and im3_1 81
75 1-benzyl-2-(7-benzyl-5,6-dimethyl-7H-pyrrolo-[2,3-d] pyrimidine-4-base-amino)-4,5-dimethyl-1H-pyrroles-3-formonitrile HCN C29H28N6 460.5867 4 Im2_1 and im3_1 49
Table 3 physical-chemical property
The embodiment numbering Molecular weight LC t R MS [M+H] +Or [M-H] - The NMR method The NMR spectrum Fusing point (℃)
1 245.71 3,17 246 1H NMR，300 MHz，DMSO-d6 (ppm)： 7.52(d，2H)，7.38(s，1H)，7.23(m，1 H)， 5.46(s，2H)，1.91(s，3H)，1.74(s，3 H) 148-150
2 273.72 2,97 274 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.83(s，1H)，7.71(s，1H)，7.55(m， 3H)， 7.36(m，1H)，2.29(s，3H)，2.07(s，3 H) 288-291
3 292.17 3,32 292 1H NMR，300 MHz，DMSO-d6 (ppm)： 7.60(m，4H)，7.44(m，1H)，2.43(s，3 H)， 2.23(s，3H) 158-161
4 516.01 3.60 514 1H NMR，300 MHz，DMSO-d6 (ppm)： 8.54(s，1H)，8.07(d，1H)，7.95(s，1H)， 7.71-7.47(m，5H)，7.36(d，1H)，6.48(s， 1H)，2.40(s，3H)，2.17(s，3H)，1.34(s， 9H) 189-190
5 287.75 2.52 288 1H NMR，300 MHz，DMSO-d6 (ppm)： 7.71(m，4H)，7.52(m，1H)，7.20(m， 3H)，2.49(s，3H)， 2.27(s，3H) 169-171
6 267.34 2.32 268 1H NMR，300 MHz，DMSO-d6 (ppm)： 8.15(s，1H)，7.77(s，1H)，7.23(m，3H)， 7.01(d，2H)，5.35(s，2H)，4.44(s，2H)， 2.29(s，3H)，2.13(s，3H) 195-198
7 407.86 2.76 406 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.2，10.47(bs，1H)，9(bs，2H)，8.17- 6.76(m，9H)，2.54，2.36(s，3H)，2.19， 2.09(s，3H) 105-107
8 262.36 1.91 262 1H NMR，300 MHz，DMSO-d6 (ppm)： 5.74(s，2H)，3.62(t，2H)，3.55(m，4 H)， 2.30(bs，4H)，2.17(t，2H)，1.96(s，3 H)，1.83(s，3H)， 1.66(m，2H) 135-138
9 290.37 1,63 290 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.67(s，1H)，7.72(s，1H)，4.05(t，2 H)， 3.52(m，4H)，2.23(m，12H)，1.76(m， 2H) 192,5- 195,3
10 308.81 1H NMR，300 MHz，DMSO-d6 (ppm)： 8.28(s，1H)，4.11(t，2H)，3.50(t，4H)， 2.25(m，12H)，1.77(m，2H) Oily matter
11 304.40 0,55 304 1H NMR，300 MHz，DMSO-d6 (ppm)： 8.11(s，1H)，7.67(s，1H)，4.40(s，2 H)， 4.09(t，2H)，3.53(m，4H)，2.23(m， 12H)，1.78(m，2H) 115-117
12 424.51 1,92 424 1H NMR，300 MHz，DMSO-d6 (ppm)： 10.30，9.05(bs，1H)，8.13，8.06 (s，1H)， 7.63-6.74(m，4H)，4.16，4.04 (t，2H)，3.53(bs，4H)， 2.49(s，3H)，2.34(bs，6H)， 2.20(s，3H)，1.80(m，2H) 219,4-222,4
13 453.50 2,17 453 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.50(bs，1H)，8.24-7.80(m，4 H)， 7.13(d，1H)，4.10(t，2H)，3.55 (bs，6H)，2.29(s，3H)， 2.27(s，3H)，1.81(m，2H) 158,8-161,5
14 438.53 2,54 438 1H NMR，300 MHz，DMSO-d6 (ppm)： 10.45，9.20(bs 1H)，8.20-6.78 (m，5H)， 4.16，4.05(t，2H)，3.86(s，3H)， 3.81(s，3H)， 3.55(bs，4H)，2.46(s，3H)， 2.29(bs，6H)， 2.21(s，3H)，1.18(m，2H) 201,3-205
15 502.41 2,78 501 1H NMR，300 MHz，DMSO-d6 (ppm)： 13.35(bs，1H)，8.42(s，1H)，7.17 (s，1H)，6.97(s，1H)，4.25(t，2 H)，3.55(bs，4H)，2.51，(bs，6H)， 2.40(s，3H)，2.31(s，3H)，1.90 (m，2H) 265,6-268,5
16 532.65 3.10 532 1H NMR，300 MHz，DMSO-d6 (ppm)： 8.44(s，1H)，8.38(s，1H)，8.02(m， 3H)，7.63(t，1H)，6.43(s，1H)， 4.09(t，2H)，3.49(t，4H)，2.31- 2.18(m，12H)，1.77(m，2H)， 1.32(s，9H) 120,9-125,3
17 385.47 2.84 386 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.61，10.76(s，1H)，8.60-6.97(m， 11H)，5.43，5.31(s，2H)，3.86(s， 3H)，2.39，2.31(s，3H)，2.21， 2.10(s，3H)， 214-216
18 387.44 2.73 386 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.48，10.63(s，1H)，9.39(bs，2H)， 8.24-6.80(m，10)，5.45，530(s， 2H)，3.89，3.83(s，3H)，2.48， 2.30(s，3H)，2.22，2.10(s，3H) 257-259
19 425.92 2.97 426 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.72，10.77(s，1H)，9.13-7.40(m， 13H)，2.53，2.42(s，3H)，2.20， 2.13(s，3H) 133-140
20 443.86 2.98 442 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.89，11.02(s，1H)，8.42-7.40(m， 10H)，2.45，2.40(s，3H)，2.20， 2.12(s，3H) 238-239
21 436.86 2.85 437 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.92，11.03(s，1H)，8.70-7.41(m， 10H)，2.53，2.39(s，3H)，2.20- 2.11(s，3H) 204,2-206,5
22 588.11 3.07 586 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.60，10.73(s，1H)，8.27-7.12(m， 18H)，5.19(s，4H)，2.43，2.38(s， 3H)，2.19，2.10(s，3H) 101-109
23 420.86 2.91 421 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.94，11.05(s，1H)，8.76-7.42(m， 10H)，2.53，2.40(s，3H)，2.21- 2.12(s，3H) 218-219
24 421.89 2.77 420 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.53，10.65(s，1H)，9.40(bs，1H)， 8.25-6.80(m，9H)，3.86， 3.82(s，3H)，2.53，2.50(s，3H)， 2.19，2.09(s，3H) 146-187
25 405.51 2.95 404 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.66，10.71(s，1H)，9.11-7.07(m， 14H)，5.45，5..33(s，2H)，2.43， 239(s，3H)，2.22，2.12(s，3H) 121-125
26 423.44 2.93 422 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.83，10.96(s，1H)，8.40-7.06(m， 11H)，5.44，5.33(s，2H)，2.40， 2.33(s，3H)，2.23，2.12(s，3H) 165-166
27 361.47 2.80 362 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.30，10.83(s，1H)，8.50-7.05(m， 10H)，5.43，5.30(s，2H)，2.44， 2.30(s，3H)，2.22，1.98(s，3H) 170-172
28 416.44 2.83 415 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.70(bs，1H)，10.9(bs，1H)，8.27- 7.05(m，11H)，5.36(s，2H)，2.34(s， 3H)，2.14(s，3H) 202-205
29 399.50 2.86 398 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.43，10.46(s，1H)，8.7(bs，1H)， 8.17-7.05(m，9H)，5.42，5.29(s， 2H)，2.43，2.30(s，3H)，2.21(s， 6H)，2.19，2.09(s，3H) 237-240
30 567.70 3.04 566 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.53，10.67(s，1H)，8.24-7.05(m， 20H)，5.43，5.31(s，2H)，5.18(s， 4H)，2.38，2.31(s，3H)，2.21， 2.09(s，3H) 159-160
31 398.52 2.87 397 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.43，10.43(s，1H)，8.20-6.72(m， 11H)，5.42，5.29(s，2H)，2.96(s， 6H)，2.43，2.29(s，3H)，2.21， 2.08(s，3H) 219-221
32 400.44 2.84 399 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.88，10.99(s，1H)，8.75-7.06(m， 11H)，5.45，5.33(s，2H)，2.43， 2.33(s，3H)，2.24，2.12(s，3H) 103-109.5
33 401.47 2.76 400 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.47，10.61(s，1H)，9.38(bs，1H)， 8.23-6.79(m，10)，5.42，530(s， 2H)，3.86，3.81(s，3H)，2.47， 2.30(s，3H)，2.21，2.09(s，3H) 220-221
34 397.53 2.93 398 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.60，10.69(s，1H)，8.30-7.05(m， 11H)，5.43，5.31(s，2H)，2.91(m， 1H)，2.42，2.31(s，3H)，2.22， 2.10(s，3H)，1.22(d，6H) 196-197
35 380.46 2.83 381 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.87，11.0(s，1H)，8.35-7.06(m， 11H)，5.36(s，2H)，2.35(s，3H)， 2.15(s，3H) 223.5-225
36 419.92 2.86 420 1H NMR，300 MHz，DMSO-d6 (ppm)： 11.50，10.52(s，1H)，8.62(bs，1H)， 8.18-7.26(m，8H)，2.54，2.37(s， 3H)，2.20(s，6H)，2.20，2.09(s，3H) 139-212
37 400.87 2.92 399. 1H NMR，300 MHz，DMSO-d6 (ppm)： 12(ds，1H)，8.38-7.39(m，10H)， 2.41(s，3H)，2.14(s，3H) 226-227.5
38 495.77 3.45 (46.65 ％)， 3.75 (45.64 ％) 493 1H NMR，300 MHz，DMSO-d6 (ppm)： 12.45(s，1H)，10.58(s，1H)，8.69(s， 1H)，7.98(s，1H)，7.60(m，3H)， 7.42(m，2H)，6.83(d，1H)，2.57(s， 3H)，2.19(s，3H) 292-294.5
39 416.87 3.20 (70.73 ％)， 3.43 (29.27 ％) 415 1H NMR，300 MHz，DMSO-d6 (ppm)： 12.31(s，1H)，10.46(s，1H)，8.44(d， 1H)，7.94(s，1H)，7.60(m，3H)， 7.46(s，1H)，7.25(t，1H)，7.00(t， 1H)，6.87(d，1H)，2.50(s，3H)， 2.18(s，3H) 281-293
40 451.32 3.42 (36.77 ％)， 3.69 (53.69) 449 1H NMR，300 MHz，DMSO-d6 (ppm)： 12.3(bs，1H)，10.58(s，1H)，8.53(s， 1H)，7.98(s，1H)，7.60(m，3H)， 745(s，1H)，7.28(d，1H)，6.87(d， 1H)，2.58(s，3H)，219(s，3H) 314-315
41 485.76 3.52 483 1H NMR，300 MHz，DMSO-d6 (ppm)： 13.89(s，1H)，11.81(bs，1H)， 8.41(s，1H)，7.61(m，3H)，7.43(m， 2H)，7.14(d，1H)，2.58(s，3H)， 2.24(s，3H) 284-285
42 430.90 3.28 (68.85 ％)， 3.55 (31.15 ％) 431 1H NMR，300 MHz，DMSO-d6 (ppm)： 12.32(bs，1H)，10.35(s，1H)， 8.37(s，1H)，7.93(s，1H)，7.60(m， 3H)，7.44(dd，1H)，7.06(d，1H)， 6.75(d，1H)，2.59(s，3H)，2.28(s， 3H)，2.18(s，3H) 302-303
43 434.86 3.29 (67.04 ％)， 3.51 (31.34 ％) 435 1H NMR，300 MHz，DMSO-d6 (ppm)： 12.2(bs，1H)，10.65(s，1H)，8.44(s， 1H)，8.00(s，1H)，7.60(m，3H)， 7.46(s，1H)，7.26(d，1H)，6.94(d， 1H)，2.54(s，3H)，2.19(s，3H) 271-279
44 500.87 3.45 (71.15 ％)， 3.67 (28.85 ％) 499 1H NMR，300 MHz.DMSO-d6 (ppm)： 12.2(bs，1H)，10.65(s，1H)，8.44(s， 1H)，8.00(s，1H)，7.60(m，3H)， 7.46(s，1H)，7.26(d，1H)，6.94(d， 1H)，2.54(s，3H)，2.19(s，3H) 262-276
45 475.35 3.27 (28.50 ％)， 3.64 (66.65 ％) 473 1H NMR，300 MHz，DMSO-d6 (ppm)： 12.3(bs，1H)，10.56(s，1H)，8.67(s， 1H)，8.06(s，1H)，7.32(m，4H)， 7.09(d，2H)，6.82(d，1H)，5.42(s， 2H)，2.50(s，3H)，2.21(s，3H) 288-290
46 396.46 3.00 (27.06 ％)， 3.35 (71.55 ％) 397 1H NMR，300 MHz，DMSO-d6 (ppm)： 12.26(bs，1H)，10.43(s，1H)， 8.42(s，1H)，8.02(s，1H)，735- 6.84(m，8H)，5.41(s，2H)，2.50(s， 3H)，2.20(s，3H) 292-293
47 476.52 3.19 (26.81 ％)， 5.68 475 1H NMR，300 MHz，DMSO-d6 (ppm)： 12.23(bs，1H)，10.44(s，1H)， 8.81(s，1H)，8.00(s，1H)，7.49(dd， 1H)，7.29(m，3H)，7.09(d，2H)， 6.76(d，1H)，5.42(s，2H)，2.49(s， bomlik
(65.39 ％) 3H)，2.20(s，3H)
48 430.90 3.24 (27.04 ％)， 3.59 (66.89 ％) 429 1H NMR，300 MHz，DMSO-d6 (ppm)： 12.3(bs，1H)，10.55(bs，1H)， 8.51(s，1H)，8.06(s，1H)，7.28(m， 4H)，7.07(m，2H)，6.86(d，1H)， 5.42(s，2H)，4.99(s，3H)，2..49(s， 3H)，2.21(s，3H) 302-303
49 465.35 3.38 465 1H NMR，300 MHz，DMSO-d6 (ppm)： 13.79(s，1H)，12(bs，1H)，8.46(s， 1H)，7.26(m，4H)，7.08(d，2H).， 6.96(s，1H)，5.46(s，2H)，2.50(s， 3H)，2.26(s，3H) 299
50 465.35 3.34 465 1H NMR，300 MHz，DMSO-d6 (ppm)： 13.86(s，1H)，11.82(s，1H)，8.48(s， 1H)，7，40-7.07(m，7H)，5.46(s， 2H)，2.49(s，3H)，2.26(s，3H) 298
51 450.59 3.49 449 1H NMR，300 MHz，DMSO-d6 (ppm)： 8.23(s，1H)，8.05(s，1H)，7.62(d， 2H)，7.40-7.22(m，6H)，7.03(d， 2H)，6.44(s，1H)，5.36(s，2H)， 2.26(s，3H)，2.16(s，3H)，1.33(s， 9H) 165-168
52 495.59 3.57 494 1H NMR，300 MHz，DMSO-d6 (ppm)： 8.4(bs，1H)，8.24(d，2H)，8.02(d， 2H)，7.99(s，1H)，7.25(m，3H)， 7.04(d，2H)，6.50(s，1H)，5.36(s， 2H)，2.36(s，3H)，2.18(s，3H)， 1.33(s，9H) 219.5-221
53 495.59 3.53 494 1H NMR，300 MHz，DMSO-d6 (ppm)： 8.51(s，1H)，8.05(d，1H)，7.98(s， 1H)，7.65(t，1H)，7.26(m，3H)， 7.00(m，2H)，6.46(s，1H)，5.36(s， 2H)，2.34(s，3H)，2.16(s，3H)， 1.34(s，9H) ＞200 decompose
54 468.5 3.54 467 1H NMR，300 MHz，DMSO-d6 (ppm)： 8.34(s，1H)，8.35(s，1H)，8.47- 7.20(m，6H)，7.05(m，3H)，6.44(s， 1H)，5.37(s，2H)，2.36(s，3H)， 2.17(s，3H)，1.32(s，9H) 153-156
55 471.0 3.57 471 1H NMR，300 MHz，DMSO-d6 (ppm)： 8.33(s，1H)，8.00(s，1H)，7.65- 7.52(m，4H)，7.37(m，6H)，7.25(t， 1H)，6.44(s，1H)，2.34(s，3H)， 2.15(s，3H) 169-176
56 489.0 3.62 489 1H NMR，300 MHz，DMSO-d6 (ppm)： 8.43(s，1H)，7.98(s，1H)，7.60- 7.36(m，7H)，7.09(t，1H)，6.45(s， 1H)，2.38(s，3H)，2.17(s，3H)， 1.33(s，9H) 189-191.5
57 516.0 3.64 514.2 1H NMR，300 MHz，DMSO-d6 (ppm)： 8.60(s，1H)，8.27(d，2H)，7.95(m， 3H)，7.56(m，3H)，7.38(m，1H)， 6.50(s，1H)，2.42(s，3H)，2.18(s， 3H)，1.34(s，9H) 195-198
58 494.6 3.51 495.2 1 1H NMR，300 MHz，DMSO-d6 (ppm)： 8.32(s，1H)，8.07(s，1H)，7.42(m， 3H)，7.26(m，3H)，7.07(m，3H)， 6.43(s，1H)，5.31(s，2H)，2.69(bs， 2H)，2.49(bs，2H)，1.71(bs，4H)， 1.32(s，9H) 147-153
59 476.6 3.47 475.2 6 1H NMR，300 MHz，DMSO-d6 (ppm)： 8.21(s，1H)，8.09(s，1H)，7.59(d， 2H)，7.41-7.20(m，6H)，7.08(d， 2H)，6.41(s，1H)，5.30(s，2H)， 2.63(bs，2H)，2.49(bs，2H)， 1.70(bs，4H)，1.32(s，9H) 188-190
60 501.4 2.92 1H NMR， 10.10；9.80(s，1H，NH)， 234,3-237,2
CDCl3 ppm 7.51-7.19 (m, 9H, aromatics-H), 2.55 (s, 3H, CH3), 2.36 (s, 3H, CH3), 2.30 (s, 3H, CH3), 2.24 (s, 3H, CH3)
61 507.0 2,98 507 1H NMR， CDCl3 ppm 10.06; 9.84 (s, 1H, NH), 7.50-7.22 (m, 10H, aromatics-H), 5.38 (s, .2H, CH2), 3.09; 2.90 (bs, 2H, 1 -H2), 2.61; 2.59 (s, 3H, CH3), 2.57 (bs, 2H, 4 -H2), 2.27; 2.24 (s, 3H, CH3), 1.88; 1.80 (bs, 4H, 2 -, 3 -H2) 203,7-204,7
62 605.1 3,06 605 1H NMR， CDCl3 ppm 10.10 (bs, 1H, NH), 7.53-7.04 (m, 10H, aromatics-H), 5.43 (s, 2H, CH2), 2.60 (s, 2H, CH2), 2.27 (s, 3H, CH3) 187,4-189,3
63 481.0 2,94 481 1H NMR， CDCl3 ppm 10.10 (s, 1H, NH), 7.50-7.18 (m, 10H, aromatics-H), 5.46 (s, 2H, CH2), 2.60 (s, 3H, CH3), 2.46 (s, 3H, CH3), 2.28 (s, 3H, CH3), 2.26 (s, 3H, CH3) 228,1-229,0
64 503.0 3,06 502 1H NMR， CDCl3 ppm 10.45 (s, 1H, NH), 8.20 (d, 1H, 7-H, 3J=7.8Hz), 7.61-7.25 (m, 13H, aromatics-H, 5.72 (s, 2H, CH2), 2.56 (s, 3H, CH3), 2.28 (s, 3H, CH3) 252,2-253,1
65 508.6 2,97 509 1H NMR， CDCl3 ppm 10.64 (s, 1H, NH), 8.55 (d, 1H, 7-H, 3J=7.8Hz), 7.55-7.21 (m, 14H, aromatics-H), 5.75 (s, 2H, CH2), 5.50 (s, 2H, CH2), 4.93 (bs, 2H, 1 '-H2), 2.61 (bs, 2H, 4 '-H2), 1.91 (bs, 2H, 2 ', 3 '-H2) 254,6-255,6
66 606.7 3,03 607 1H NMR， CDCl3 ppm 10.43 (s, 1H, NH), 8.56 (d, 1H, 7-H, 3J=7.8Hz), 7.50-7.13 (m, 24H, aromatics-H), 5.76 (s, 2H, CH2), 5.53 (s, 2H, CH2) ＞90 decompose
67 482.5 2,89 483 1H NMR， CDCl3 ppm 10.47; 10.20 (s, 1H, NH), 8.54; 8.42 (d, 1H, 7-H, 3J=7.8 Hz), 7.60-7.16 (m, 14H, aromatics-H), 5.73 (s, 2H, CH2), 5.69; 5.53 (s, 2H, CH2), 2.46 (s, 3H, CH3), 2.23 (s, 3H, CH3) ＞90 decompose
68 507.0 3,01 507 1H NMR， CDCl3 ppm 10.05; 9.87 (s, 1H, NH), 7.54-7.00 (m, 10H, aromatics-H), 5.41; 5.40 (s, 2H, CH2), 2.86 (bs, 2H, 7-H2), 2.63 (bs, 2H, 10-H2), 2.50 (s, 3H, CH3), 2.49 (s, 3H, CH3), 1.78 (bs, 4H, 8-, 9-H2) 220,1-221,5
69 512.6 3,02 513 1H NMR， CDCl3 ppm 10.10; 9.92 (s, 1H, NH), 7.33-7.11 (m, 11H, aromatics-H), 5.41 (s, 2H, CH2), 5.33 (s, 2H, 216,219,9
CH2)，3.06；2.90(bs，4H，1′，1″- H2)， 2.57(bs，4H，4′，4″-H2)，1.86(bs， 8H，2′，2″-，3′，3″-H2)
70 610.7 3,08 611 1H NMR， CDCl3 ppm 10.2 (bs, 1H, NH), 7.33-7.03 (m, 21H, aromatics-H), 5.46 (s, 2H, CH2), 5.40 (s, 2H, CH2), 2.93 (bs, 2H, 7-H2), 2.58 (bs, 2H, 10-H2), 1.77 (bs, 4H, 8-, 9-H2) 191,0-191,7
71 486.6 2,99 487 1H NMR， DMSO d6 ppm 9.67 (s, 1H, NH), 7.35-7.07 (m, 11H, aromatics-H), 5.42 (s, 2H, CH2), 5.32 (s, 2H, CH2), 2.92 (bs, 2H, 7-H2), 2.50 (bs, 5H, 10-H2, CH3), 2.49 (s, 3H, CH3), 1.74 (bs, 4H, 8-, 9-H2) 225-229,5
72 481.0 2,88 481 1H NMR， CDCl3 ppm 9.98 (s, 1H, NH), 7.51-7.03 (m, 10H, aromatics-H), 5.46 (s, 2H, CH2), 2.51 (s, 3H, CH3), 2.29 (s, 3H, CH3), 2.24 (s, 3H, CH3), 2.19 (s, 3H ,-CH3) 237,9-240,5
73 486.6 3,06 487 1H NMR， CDCl3 ppm 10.00; 9.90 (s, 1H, NH), 7.32-7.06 (m, 11H, aromatics-H), 5.48; 5.45 (s, 2H, CH2), 5.35; 5.32 (s, 2H, CH2), 3.12; 2.90 (bs, 2H, 1 are " H2); 2.55 (4 " H2) for bs, 2H, 2.52 (s, 3H, CH3), 2.24 (s, 3H, CH3), 1.86 (bs, 4H, 2 ", 3 " H2) 248,9-249,6
74 584.7 3,11 585.2 9 1H NMR， CDCl3 ppm 10.01 (bs, 1H, NH), 7.31-7.04 (m, 21H, aromatics-H), 5.50 (s, 2H, CH2), 5.41 (s, 2H, CH2), 2.53 (s, 3H, CH3), 2.26 (s, 3H, CH3) 197,1-197,6
75 460.5 2,88 461 1H NMR， CDCl3 ppm 10.11; 9.90 (s, 1H, NH), 7.33-7.09 (m, 11H, aromatics-H), 5.50; 5.46 (s, 2H, CH2), 5.40 (s, 2H, CH2), 2.51 (s, 3H, CH3), 2.44 (s, 3H, CH3), 2.25 (s, 3H, CH3), 2.22 (s, 3H, CH3) 236,0-239,1
76 248.3306 1.56 249 1H NMR，300 MHz，DMSO- d6 (ppm)： 11.63(s，1H)，7.74(s，1H)，4.05(t，2H)，2.22(s，3H)，2.21(s， 3H)，2.18(t，2H)，2.11(s，6H)，1.74(q，2H) 165- 166.5
77 266.7762 2.22 267 1H NMR，300 MHz，DMSO- d6 (ppm)： 8.47(s，1H)，4.23(t，2H)，2.40(s，3H)，2.36(s，3H)，2.21(t，2H)， 2.13(s，6H)，1.80(q，2H) Oily matter
78 262.3605 0.56 263 1H NMR，300 MHz，DMSO- d6 (ppm)： 8.86(bs，1H)，8.12，7.67(s，1H)，4.39，4.11(bs，2H)，4.07(t， 2H)，2.27(s，3H)，2.25(s，3H)，2.17(t，2H)，2.10(s，6H)，1.77- 1.71(q，2H) 90-92
79 396.4963 2.02 397 1H NMR，300 MHz，DMS0- d6 (ppm)： 11.36，10.47(s，1H)，9.27(bs，1H)，8.19-6.76(m，5H)，4.13， 4.01(t，2H)，3.84，3.79(s，3H)，2.48-2.11(m，14H)，1.76(q， 2H) 195.6- 196.4
80 382.4692 1.91 383 1H NMR，300 MHz，DMSO- d6 (ppm)： 11.30，10.25(bs，1H)，9.11(bs，2H)，8.12-6.73(m，5H)，4.13， 4.01(t，2H)，2.48-2.11(m，14)，1.76(q，2H) 185
81 475.6422 2.92 476 H NMR，300 MHz，DMS0- d6 (ppm)： 8.04(s，1H)，7.99(s，1H)，7.46(d，2H)，6.92(d，2H)，6.36(s， 1H)，4.07(t，2H)，3.71(s，3H)，2.26(s，3H)，2.21(s，3H)，2.16(t， 2H)，2.09(s，6H)，1.72(q，2H)，1.30(s，9H) 91.7- 93.6
82 475.6422 2.99 476 1H NMR，300 MHz，DMSO- d6 (ppm)： 8.12(s，1H)，8.03(s，1H)，7.26(t，1H)，7.16(m，2H)，6.80(d， 1H)，6.39(s，1H)，4.08(t，2H)，3.60(s，3H)，2.27(s，3H)，2.24(s， 3H)，2.15(t，2H)，2.09(s，6H)，1.72(q，2H)，1.30(s，9H) 102- 104
83 490.6133 3.04 491 1H NMR，300 MHz，DMSO- d6 (ppm)： 8.61-7.64(m，6H)，6.45(s，1H)，4.08(t，2H)，2.32(s，3H)， 2.28(s，3H)，2.16(t，2H)，2.10(s，6H)，1.73(q，2H)，1.33(s，9H) 164.4- 166
84 226.2833 3.30 227 1H NMR，300 MHz，DMSO- d6 (ppm)： 7.86(t，1H)，7.29(d，1H)，7.17(d，1H)，5.67(s，2H)，2.49(s， 3H)，1.92(s，3H) 1.87(s，3H) Oily matter
85 254.2939 2.59 255 1H NMR，300 MHz，DMSO- d6 (ppm)： 11.82(s，1H)，7.88(t，1H)，7.71(s，1H)，7.33(d，2H)，2.49(s， 3H)，2.28(s，3H)，2.14(s，3H) 298.5- 300
86 272.7395 3.79 273 1H NMR，300 MHz，DMSO- d6 (ppm)： 8.47(s，1H)，7.97(t，1H)，7.49(d，1H)，7.44(d，1H)，2.53(s， 3H)，2.45(s，3H)，2.34(s，3H) 198.3- 198.7
87 268.3238 2.05 269 1H NMR，300 MHz，DMSO- d6 (ppm)： 8.10(s，1H)，7.89(t，1H)，7.86(bs，1H)，7.41(d，1H)，7.31(d， 1H)，4.47(s，2H)，2.50(s，3H)，2.35(s，3H)，2.23(s，3H) 214.3- 215.5
88 388.4326 2.60 389 1H NMR，300 MHz，DMSO- d6 (ppm)： 11.50，10.45(s，1H)，9.1(bs，2H)，8.18-6.77(m，8H)，2.54， 2.36(s，3H)，2.28(s，3H)，2.17(s，3H) 264.2- 264.8
89 417.4307 2.88 418 1H NMR，300 MHZ， DMS0- d6 (ppm)： 1.74(s，1H)，11.27，10.74(bs，1H)，8.38-7.16(m，8H)，2.45， 2.27(s，3H)，2.4(s，3H)，2.19(s，3H) 216.5- 217
90 496.5766 4.65 497 1H NMR，300 MHz，DMSO- d6 8.6-7.26(m，9H)，6.51(s，1H)，2.53(s，3H)，2.40(s，3H)，2.26(s， 3H)，1.34(s，9H) 108- 110
d6 (ppm)：
91 481.6056 4.49 482 1H NMR，300 MHz，DMSO- d6 (ppm)： 8.23(s，1H)，8.04(s，1H)，7.89(t，1H)，7.52(d，2H)，7.41(d， 1H)，7.32(d，1H)，6.95(d，2H)，6.41(s，1H)，3.73(s，3H)， 2.53(s，3H)，2.31(s，3H)，2.24(s，3H)，1.32(s，9H) 221.5- 222.4
92 517 4.49 482 1H NMR，300 MHz，DMSO- d6 (ppm)： 8.23(s，1H)，8.04(s，1H)，7.89(t，1H)，7.52(d，2H)，7.41(d， 1H)，7.32(d，1H)，6.95(d，2H)，6.41(s，1H)，3.73(s，3H)， 2.53(s，3H)，2.31(s，3H)，2.24(s，3H)，1.32(s，9H) 97-98
Embodiment 93 (drug efficacy study)
By of the inhibition of rat tracheae external beam radiotherapy immunoassay (RIA) method detection of active material to P material (SP) release
In external environment, the rat tracheae in the biological bath (biological bath) (using the Wistar rat of body weight 200-250g) detection of active material is discharged (500 * 10-9mol) influence to SP.With the perfusion of the Ke Nuobushi solution (Krebs ' s solution) of oxygenation after 1 hour, sampling is 3 times in 8 minutes.With the electric current of 10Hz, 40V, 0.1ms, the middle period stimulatory organs 120s at 8 minutes.SP content by special radioimmunoassay method working sample.Represent observed value by following mode in the accompanying drawings: blank post is represented the observed value before the electricity irritation, and the observed value that the black post records after representing to stimulate immediately, shade post are represented the observed value of electricity irritation after 8 minutes.Use following radioimmunoassay method: with iodine isotope I 125The single iodate SP of the 5000cpm of mark is as the RIA tracer.The working concentration scope is that the synthetic SP of 0-100fmol (phentomoles)/ml makes standard.With respect to the neuropeptide concentration of sample tissue weight in wet base with " fmol/mg " unit representation.Fig. 8 represents that reference material TT-232 and concentration are the restraining effect (see black post) of 8 kinds of compounds of 500nM to P material release under the electricity irritation.Accompanying drawing has shown the remarkable value with respect to the control group income value, and control group is only used solvent treatment sample organ.
Embodiment 94 (drug efficacy study)
Inhibiting detection to neurogenic inflammation in the body
(capsaicine inductive mice ear and plasma proteins exosmose)
The male BALB/c mouse of 18-20g is anaesthetized with ketamine (100mg/kg used according to the invention) and xylazine (10mg/kgi.m.).Behind the measuring basis ear thickness, press the amount of 0.1ml/10g according to the present invention and use test substance.Behind the 10min in the tail vein injection Evans Blue dyestuff 125mg/kg (2.5% solution, 0.05ml/10g), the left ear to every animal behind the 5min uses 10 μ l, 96% ethanol, auris dextra uses 10 μ l, 2.5% capsaicine solution.The Evans Blue labeling dye combines with plasma albumin in working cycle.Because inflammatory effect is left the place of blood vessel, the surface becomes blueness at plasma albumin.Measure ear thickness behind the 30min once more, represent the swelling degree with the per-cent of original depth.By the sacrificed by exsanguination animal, its ear is downcut and measure ear weigh subsequently.With the 1.5ml methane amide under 20 ℃ through extracting cumulative dyestuff in the tissue in 72 hours.Measure the optical density(OD) of solution in 620nm wavelength place with spectrophotometer (having the microplate reader).The amount of dye of exosmosing (amount of expression plasma albumin) is with the unit representation of the every tissue wet amount of mg/.All deduct the observed value of the ear of Ethanol Treatment with the observed value of the ear of Capsaicin Treatment for two kinds of animals.With the animal of solvent treatment in contrast.Fig. 9 shown give reference substance TT-232 and give 100 μ g/kg, 11 kinds of compounds of the present invention after, use the Evans Blue semi-invariant of the control group (black post) of solvent treatment in advance.Distribution free is graceful-and Whitney (Mann-Whitney) check is used for result's statistical evaluation.*p＜0.05；**p＜0.01。
Embodiment 95 (drug efficacy study)
Mouse ear vasodilation of tori seed oil inductive and plasma proteins extravasation detection.
With ketamine (100mg/kg used according to the invention) and the male Balb/c mouse of xylazine (5mg/kg i.m.) anesthesia, i.v. gives and gives 0.1ml iodine isotope I then 125The albumin of mark (30kBq activity/mouse).Drip 10 μ l, 1% tori seed oil to the left ear two sides of every mouse, be coated with out then.Above ear, measure radioactivity, measure 50min with the gamma-ray counter per minute.Radioactive increase shows vasodilation and plasma protein extravasation.According to the present invention, before tori seed oil is handled, give 20 μ g/kg TT-232 and non-peptide and follow the tracks of molecule (non peptidefollowing molecule) 11527 (10 and 100 μ g/kg).Control group uses solvent.
ANOVA analyzes the back and uses Bang Fulangni (Bonferroni) modified survey method to carry out statistical evaluation.* p＜0.05; * p＜0.01; Every group of n=7 (see figure 10).
Embodiment 96 (drug efficacy study)
Neuropathic hyperpathia detects
The one-sided part ligation (ligation) of sciatic nerve (n.ishiadicus) causes the mechanical wounding of limbs to experience threshold value reduction (Seltzer operation).Detect mechanical nociception (Randall-Selitto test) with Ugo Basile analgesimeter.The pawl of animal is placed under the tetrafluoroethylene cone of circular distal, and apply the power that increases gradually to central zone, pawl back (beck).Value when animal is pulled out leg is a pain threshold.Can read this value with manual mode with " gram " by linear graduation (beforelinear scale).The variation of machinery threshold value is represented with the per-cent of initial threshold own.After contrasting measurement, anaesthetize the sciatic side of male Spague-Dawley rat thigh with Sodital, isolate the 1/3-1/2 partial nerve then carefully, with its no wound line (Mersilene with 6/0 size, Ethicon) fasten, then closure of incisions.Operation back the 7th day is measurement mechanical nociception threshold value once more.Only reduce at least 20% animal and carry out subsequently detection compare threshold value with results of comparison.Give compound 18 20min replicate measurements afterwards of the present invention.Experimental result to be representing (being represented by white post) with respect to the per-cent of the initial value of being surveyed before the administration, and with the solvent control group relatively.Use distribution free graceful-the Whitney method of inspection determines statistical significant difference.* p＜0.05, * * p＜0.01, every group of n=6-8 (seeing Figure 11).

Claims (11)

1. the 7H-pyrrolo-of general formula (I) [2,3-d] pyrimidine derivatives and treat acceptable salt is characterized in that in the structural formula
R1 is the alkyl of 1-4 carbon atom of alkyl, morpholino-contain of 1-4 the carbon atom of alkyl, heteroaryl-contain of 1-4 carbon atom of alkyl, aryl, heteroaryl, aryl-contain or dialkyl amido-the contain alkyl of 1-4 carbon atom,
R2, R3 are hydrogen, methyl, ethyl, propyl group, sec.-propyl or cyclopropyl independently of one another, and perhaps R2 and R3 become tetramethylene together.
R4 is
Perhaps Perhaps ,
Wherein
R5 for replace or unsubstituted aromatic ring or hetero-aromatic ring,
Wherein
R6, R7, R8 and R9 are hydrogen, halogen, nitro, amino, alkylamino, dialkyl amido, hydroxyl, methoxyl group, oxyethyl group, isopropoxy or alkylsulfonyl independently of one another,
R10 is hydrogen or itrile group,
R11 is hydrogen, methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl or the tetramethylene ring that links to each other with X,
R12 is the alkyl of 1-4 carbon atom of alkyl, morpholino-contain of 1-4 carbon atom of alkyl, aryl, heteroaryl, aryl-contain or dialkyl amido-the contain alkyl of 1-4 carbon atom,
If R11 is the tetramethylene ring that links to each other with X, then X is a carbon, and in addition X is nitrogen, methyne, methyl-methyne, ethyl-methyne, propyl group-methyne, sec.-propyl-methyne, cyclopropyl-methyne, the tertiary butyl-methyne or phenyl-methyne.
2. the general formula of claim 1 (I) compound, the structure that it is characterized in that described compound is corresponding to general formula (Ia), and wherein R1, R2, R3, R10, R11, R12 and X are described identical with claim 1.
3. the general formula of claim 1 (I) compound, the structure that it is characterized in that described compound is corresponding to general formula (Ib), and wherein R1, R2, R3 and R5 are described identical with claim 1.
4. the general formula of claim 1 (I) compound, the structure that it is characterized in that described compound is corresponding to general formula (Ic), and wherein R1, R2, R3, R6, R7, R8 and R9 are described identical with claim 1.
5. a pharmaceutical preparation is characterized in that described pharmaceutical preparation contains general formula (I) compound and treatment acceptable additive.
6. the pharmaceutical preparation of claim 5 is characterized in that described pharmaceutical preparation can be used as anti-inflammatory or analgesic.
7. the pharmaceutical preparation of claim 5 is characterized in that described pharmaceutical preparation can be used as and alleviates the hyperalgesic medicine of neuropathic.
8. the pharmaceutical preparation of claim 5 is characterized in that described pharmaceutical preparation can be used as the medicine that alleviates rheumatic arthritis.
9. the pharmaceutical preparation of claim 5 is characterized in that described pharmaceutical preparation can be used as the medicine that prevents bone destruction or cartilage destruction.
10. the pharmaceutical preparation of claim 5 is characterized in that described pharmaceutical preparation can be used for treating the disease relevant with inflammatory process, as asthma, eczema or psoriatic.
11. the 7H-pyrrolo-[2 of preparation general formula (I), 3-d] method of pyrimidine derivatives, it is characterized in that by 3-hydroxyl-2-butanone and etc. the amine of molar equivalent and the compound that propane dinitrile makes general formula (II), R1 wherein, R2 and R3 are with identical described in the general formula (I), the formic acid that described compound and 5-10 times of quality is excessive mixes 1 hour to 2 days time under reflux temperature, then mixture is poured in the frozen water, the product that is settled out is separated, dry, reacted 0.5-4 hour under reflux temperature with the excessive phosphoryl chloride of 5-10 times of quality then, then extremely on ice with mixture, with the wherein R1 that is settled out, R2, the imido chlorine of the described identical general formula (III) of R3 and general formula (I) separates, and make its drying, evaporation, then
A) the imido chlorine with general formula (III) is dissolved in the aprotic solvent, and made the general formula (II) of itself and equivalent or the reaction of amine (IV) 0.5-6 hour, its formula of (II) or R1 (IV) and R3 are same as described above, add 2-10 times of molar equivalent excessive N aH simultaneously, with the gained mixture extremely on ice, the product that separation and purifying are settled out
Perhaps
B) in the polar organic solvent medium, imido chlorine and the 2-10 times of hydrazine hydrate reaction that molar equivalent is excessive with thus obtained general formula (III), reaction product in the organic phase is separated from mixture, dry, evaporation organic phase, with non-polar solvent organic phase is ground then, the hydrazine derivative of Sheng Chenging mixes with polar organic solvent thus, and the aldehyde that makes itself and equivalent was 20-120 ℃ of reaction 1-12 hour, reaction product isolated then
Perhaps
C) will be by method B) hydrazine derivative of preparation mixes with polar organic solvent, and reacts, then reaction product isolated with the isatin of equivalent.
CNA2005800206893A 2004-04-29 2005-04-25 7h-pyrrolo[2,3-d]pyrimidine derivatives, as well as their therapeutically acceptable salts, pharmaceutical preparations containing them and process for production the active agent Pending CN1972946A (en)

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